This research study is designed to test the use of ranolazine in patients with angina (chest discomfort due to reduced blood supply to the heart) due to microvascular coronary dysfunction (MCD; abnormalities in the small blood vessels of the heart). This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina. The FDA has approved this drug based on studies primarily on patients with chronic angina with major blockages of the arteries.

a) CMRI perfusion and diastolic function; b) Quality of Life (SF-36, DASI) and healthcare costs; c) hemoglobin A1C, HOMA and BNP in 134 subjects with signs and symptoms of ischemia but no obstructive CAD. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

To determine if improvement in the SAQ is positively related to improvement in CMRI myocardial ischemia in subjects with signs and symptoms of ischemia but no obstructive CAD. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Angina frequency domain of the SAQ [ Time Frame: 2 years ] [ Designated as safety issue: No ]

147 subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing.

Drug: Ranolazine

This drug is approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic angina.

1,000 mg po bid for 2 weeks

Other Name: Ranexa

Placebo Comparator: Placebo

147 subjects will undergo baseline testing and then be randomized into a clinical cross-over trial of stepped dosing of ranolazine or placebo 1,000 mg po bid for 2 weeks with exit testing followed by cross-over to the alternate ranolazine or placebo and repeat exit testing.

Drug: Placebo

1,000 mg po bid for 2 weeks

Detailed Description:

This is a randomized, double-blinded, placebo- controlled, and cross-over clinical trial. 147 subjects will be enrolled at two clinical sites with 74 subjects at Cedars-Sinai Medical Center. To maintain blinding of the investigators, the study randomization table will be kept in Pharmacy Service. The sponsor will ship the study drug directly to the Pharmacy Service. The pharmacy service will also be responsible for dispersing the study drug.

There are 4 study visits (2 visits in each study period) in this study. Subjects will be in this study for about 6 weeks from Week 0 - baseline visit to Week 6 - exit visit. Besides the procedure of study medication mentioned above, other study procedures include informed consent, physical exam, questionnaires, EKG for safety assessment, blood collection for laboratory testing, cardiac MRI, and follow-up events. In sum, participants will be asked to undergo 2 cardiac MRI's and fill out questionnaires 4 times. They will be asked to participate for 6 weeks with two 2-week courses (with a treatment window period of 5 days), one with ranolazine and the other with placebo (without knowing which they are taking). There is a 2-week washout period between treatments. The participants will otherwise remain on all their usual medications. The physicians will also be blinded to which medication the subject is receiving.

Participation in this study will be approximately 6 weeks, which consists of two 2-week study periods and in between a 2-week washout period:

During the first 2-week period: Subjects will be randomized to first receive either the ranolazine or a placebo pill (sugar pill with no active medicine). Subjects will take the extended-release ranolazine or a placebo pill for a total of 2 weeks. Subjects will take 500 mg twice daily for the first 1 week and then 1000 mg twice daily for an additional 1 week. Subjects who are unable to take the higher dose due to side effects will remain on 500 mg twice daily for the entire study period. After the 2 weeks, the participant will have a Cardiac MRI and complete study questionnaires. These tools will allow us to evaluate if the participant is doing better on the medication.

2-week washout period: Subject will then be asked to go 2 weeks without any study medication (ranolazine or placebo).

During the second 2-week period: Subject will then be given either extended release ranolazine or placebo depending on which was received the first time for a total of 2 weeks. Subjects will take 500 mg twice daily for the first 1 week and then 1000 mg twice daily for an additional 1 week. Subjects who are unable to take the higher dose due to side effects will remain on 500 mg twice daily for entire study period. This 2-week period will again be followed by a final Cardiac MRI and questionnaire completion.

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01342029